CN108586426A - A kind of alkoxy biphenyl/chalcone heterozygosis class compound, preparation method and medical usage - Google Patents

A kind of alkoxy biphenyl/chalcone heterozygosis class compound, preparation method and medical usage Download PDF

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CN108586426A
CN108586426A CN201810567025.8A CN201810567025A CN108586426A CN 108586426 A CN108586426 A CN 108586426A CN 201810567025 A CN201810567025 A CN 201810567025A CN 108586426 A CN108586426 A CN 108586426A
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methyl
phenyl
oxo
dibenzo
acrylic
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CN108586426B (en
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印晓星
谷小珂
鲁茜
杜蕾
姜艳飞
郝梦
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Xuzhou Medical University
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
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    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract

The present invention relates to a kind of alkoxy biphenyl/chalcone heterozygosis class compound, preparation method and medical usages, belong to pharmaceutical chemistry and pharmacotherapeutics field.Formulas I compound represented provided by the invention or its pharmaceutically acceptable salt prepare with it is anti-oxidant have the drug of related disorders in terms of application, the application especially in terms of preparing anti-inflammatory drug or anti-oxidation medicine.

Description

A kind of alkoxy biphenyl/chalcone heterozygosis class compound, preparation method and medicine Purposes
Technical field
The present invention relates to pharmaceutical chemistry and pharmacotherapeutics field, and in particular to a kind of alkoxy biphenyl/chalcone heterozygosis Class compound.Such compound has anti-inflammatory, oxidation resistant effect.The invention further relates to the preparation method of such compound and Contain their pharmaceutical composition.
Background technology
Oxidative stress (Oxidative Stress) refers to body cell by after the environmental stimulus of inside and outside, oxidation and antioxygen The balance changed between system of defense is destroyed, to promote intracellular reactive oxygen molecule (ROS), active nitrogen (RNS) and body fat The a large amount of generations and accumulation of matter peroxide, cause the large biological molecules such as body tissue cell and albumen and nucleic acid to damage.In addition, The generation of oxidative stress can increase the generation of inflammatory cytokine again, and then stimulate the generation of more polyradical, further damage Injured tissue cell (Biochem Pharmacol, 2015,95,156-169, Br J Pharmacol, 2015,172,1087- 1100,Toxicol Appl Pharmacol,2015,282,129-138,Kidney Int,2013,83,1029-1041).And Literature survey is shown in recent years, and oxidative stress is to lead to diabetic nephropathy, tumour, cardiovascular, immune and central nervous system disease Major reason (Anal Bioanal Chem, 2015,407,2569-2579, Eur the J Pharmacol, 2017,801,9- of disease 18,Free Radic Biol Med,2017,106,38-52).Thus, it is coped with caused by oxidative stress by research and development The drug of disease is of great significance for the prevention and treatment of disease.
Studies have shown that Keap1-Nrf2-ARE is to participate in regulation and control oxidative stress and signal of interest access (the Med Res of inflammation Rev,2016,36,924-964,Sci Rep,2015,5,12377)。Nrf2(Nuclear factor erythroid 2p45- Related factor 2) belong to CNC leucine zipper transcription activity factors family, with Antioxidation reaction, anti-inflammatory response and thin Born of the same parents' protective effect etc. is closely related.Keap1 is binding proteins of the Nrf2 in cytoplasm, and is combined with actin and be anchored to born of the same parents In slurry, the areas IVR contained are rich in cysteine, are the function point analysis areas of entire albumen.When stable state, Nrf2 levels mainly by The negative-feedback regu- lation of Keap1, Keap1 combine ubiquitin ligase Cul3 by its area BTB, Nrf2 ubiquitinations are degraded to normal water It is flat.When stress situation such as oxidative stress, Chemical stress, hyperoxia, oxidant or electrophilic body are by changing Keap1 structures As upsetting the connection between Keap1 and Nrf2, making Nrf2 separate outs, into karyon and Antioxidant responsive element ARE phase interactions With upregulation downstream relative antioxidant gene such as HO-1 in turn, the expression of NQO-1, SOD etc. play anti-inflammatory oxidation resistant effect (Pharmacol Res,2015,91,104-114).In addition, the activation of Nrf2 can also inhibit the activity of nuclear factor NF- κ B, from And inhibit inflammation generation, development (Bioorg Med Chem, 2015,23,5352-5359, J Biol Chem, 2014,289, 15244-15258).Therefore, Keap1-Nrf2-ARE signal paths become anti-oxidant and inflammation small molecule the important target of exploitation Mark.
Studies have shown that the small molecule containing michael acceptor, such as chalcone compounds, are many food plants and medium-height grass The main component of medicine, has multiple biological activities and safety is higher, and research finds that it can be by activating Keapl-Nrf2-ARE Access, and then show certain anti-oxidant and anti-inflammatory activity (Org Biomol Chem, 2015,13,3040-3047).It looks into α in your ketone structure, alpha, beta-unsaturated ketone structure are typical michael acceptors, the compound containing the class formation by with it is internal Michael addition reaction occurs for a variety of large biological molecule nucleophilic groups (sulfydryls of cysteine residues in such as Keap1), is formed Covalent bond, and then regulate and control associated signal paths, play disease prevention and cure effect (J Med Chem, 2015,58,4738- 4748).Also, the michael acceptor in chalcone structure is a kind of soft electrophilic daughter, should not by amino, hydroxy kind nucleophile into It attacks, is easy to by this kind of soft nucleophilic moieties attack of sulfydryl (J Med Chem, 2011,54,4147-4159).It wherein studies the deepest That enter is oleanolic acid derivate CDDO-Me, by building two michael acceptors to show preferable activation Nrf2 Activity, but due to thirdly phase clinic there is lethal case and be forced to stop (Nephrol Dial Transplant, 2014,29 119-124,J Med Chem,2016,59,2396-2409).But its michael acceptor structure built is still that design prevents DN Nrf2 activator provide a novel thinking.
In addition, research finds the natural products containing alcoxyl structure such as schizandrin, deoxyschizandrin, Schisandra chinensis third Element, bifendate, natural plants wood knotweed extract etc. also have bioactivity (Drug anti-inflammatory, anti-oxidant, antitumor well Metab Dispos, 2014,42,1982-1990, J Nat Prod, 2016,79,3065-3071, Acta Pharmacologica Sinica, 2016,37,382-389)。
The concern for playing anti-inflammatory antioxidation for Keap1-Nrf2-ARE in recent years is more and more but unluckily It is really to be able into be clinically used for treatment be seldom.According to its study on mechanism, mainly there is three classes drug at present (Journal of Medicinal Chemistry,2015,58,4738-4748)：(1) irreversible covalent drug, that is, pass through Covalent bond is permanently combined with its protein target.Such irreversible covalent drug has long action time, efficient and height Ligand efficiency, exactly because but they be irreversibly incorporated on protein target, so there are immune-mediated hypersensitivity Possibility, therefore such drug is not suitable for chronic administration；(2) reversible noncovalent drug passes through non-covalent bond (example Such as hydrogen bond, hydrophobic effect and Van der Waals force) and protein target Reversible binding.Such compound will not form permanent bond, Therefore it is suitable for chronic administration, while also just shows medium selectivity and activity, and with poor ligand efficiency etc. Disadvantage；(3) reversible covalent drug, it is this kind of to be newest and extensive research interest is caused due to its peculiar property.Currently, Dimethyl fumarate (DMF) with michael acceptor is the activator of Keap1/Nrf2/ARE accesses, is clinically to be used to control Treat the sole drug of multiple sclerosis.CDDO and bardoxolone methyl also belong to this one kind.Such compound overcomes can not The shortcomings that inverse covalent and reversible non-covalent drug, shows preferable bioactivity and chemical reactivity.Nevertheless, due to lacking Weary reactive compounds are combined with the reversible covalent of protein target, so reversible covalent drug is largely ignored.
Invention content
The purpose of the present invention is on the basis of existing technology, with the alkoxy biphenyl compound from schisandrin C Bifendate (DDB) is that primer utilizes new drug design on the basis of retaining the alkoxy biphenyl pharmacophore of bifendate The principles such as bioisostere, skeleton migration and prodrug design, and the cloud density etc. by changing michael acceptor makes it More easily by the sulfydryl attack of the cysteine residues of Keap1, and then designs to have synthesized and a series of there is mikey receptor structure piece Alkoxy biphenyl/chalcone heterozygosis class compound of section.Biological activity test the result shows that, such compound, which has, significant to swash Nrf2 living plays oxidation resistant effect, and activity is significantly higher than positive control medicine.
It is a further object of the present invention to provide a kind of preparation sides of above-mentioned alkoxy biphenyl/chalcone heterozygosis class compound Method.
Third object of the present invention is to provide a kind of above-mentioned alkoxy biphenyl/chalcone heterozygosis class compounds in medicine side The purposes in face.
The purpose of the present invention can be achieved by the following measures：
Alkoxy biphenyl shown in Formulas I/chalcone heterozygosis class compound or its pharmaceutically acceptable salt,
Wherein,
R1Represent hydrogen atom, cyano, nitro, hydroxyl or halogen；
R2Represent phenyl, substituted-phenyl or substitution heteroaromatic, the substituted-phenyl or substitution heteroaromatic can arbitrarily by Following substituent groups are monosubstituted or polysubstituted：C1-C4Alkoxy, C1-C4Alkyl, hydroxyl, halogen or-(CH2)nNR3R4；
N represents the integer of 1-3；
R3Or R4Separately represent C1-C6Alkyl or NR3R4It is miscellaneous that 5 to 7 yuan of substituted or non-substituted fat are formed together Ring；Its substituent group is selected from C1-C4Alkyl, phenyl or benzyl.
In a kind of preferred embodiment, R1Represent hydrogen atom, cyano or halogen.
In a kind of preferred scheme, R1Represent hydrogen atom or cyano.
N represents 1,2 or 3, it is furthermore preferred that n represents 1 or 2.
In a kind of preferred embodiment, R2Represent phenyl, substituted-phenyl or substitution heteroaromatic, the substituted-phenyl and substitution Heteroaromatic can be arbitrarily monosubstituted or polysubstituted by following identical or different substituent groups, and the substituent group is C1-C3Alkoxy, Hydroxyl, halogen or-(CH2)nNR3R4, more preferably a kind of substituent group is methoxyl group, hydroxyl or-CH2NR3R4。
In a kind of preferred embodiment, R2Represent following radicals：
Wherein, R5Represent hydrogen atom, hydroxyl or C1-C4Alkoxy；R6Or R7Separately represent hydrogen atom, C1-C4Alkane Oxygroup, halogen or-(CH2)nNR3R4。
In a kind of more preferable scheme, R5Represent hydroxyl or C1-C4Alkoxy；R6Represent hydrogen atom or-(CH2)nNR3R4；R7 Represent hydrogen atom, C1-C4Alkoxy or-(CH2)nNR3R4。
In a kind of preferred embodiment, R3And R4It may be the same or different, R3Or R4Separately represent C1-C4Alkyl, or NR3R45 to 7 yuan of substituted or non-substituted aliphatic heterocycles are formed together；Its substituent group is selected from C1-C3Alkyl, phenyl or benzyl.
In a kind of more preferable scheme, R3Or R4Separately represent C1-C3Alkyl or NR3R4Together formed substitution or 5 to 7 yuan of non-substituted aliphatic heterocycles, these 5 to 7 yuan of aliphatic heterocycles include but not limited to morpholine ring, piperazine ring, pyrrole ring or piperazine Phenazine ring；Its substituent group is selected from C1-C3Alkyl, phenyl or benzyl, such as methyl, phenyl or benzyl, especially 4- methyl or phenyls.
Further, in compound or its pharmaceutically acceptable salt described in general formula I, the compound is selected from followingization Close object：
(E) -5'- (3- (3- ((dimethylamino) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- two Methoxyl group -4,4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (3- (3,5- bis- ((dimethylamino) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7, 7'- dimethoxy-4 's, 4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (3- (3- ((diethylamino) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- two Methoxyl group -4,4' dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (3- (3- ((1- pyrrolidinyls) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- two Methoxyl group -4,4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (3- (3,5- bis- ((1- pyrrolidinyls) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7, 7'- dimethoxy-4 's, 4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (3- (3- (morpholine methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- dimethoxy-4 's, 4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (3- (3,5- bis- (morpholinyl methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- diformazans Oxygroup -4,4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (3- (3- ((4- methyl piperazines base) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- Dimethoxy-4 ', 4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (3- (3- (((4- phenyl) piperazinyl) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7, 7'- dimethoxy-4 's, 4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (3- (3- ((1- piperidyls) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- diformazans Oxygroup -4,4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (3- (3,4- dimethoxys) phenyl -3- oxo -1- acrylic) -7,7'- dimethoxy-4 's, 4'- hexichol And [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (3- (3,5- bis- ((diethylamino) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7, 7'- dimethoxy-4 's, 4' dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (2- cyano -3- (3,4- dimethoxys) phenyl -3- oxo -1- acrylic) -7,7'- dimethoxy-4 's, 4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (2- cyano -3- (4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- dimethoxy-4 's, 4'- bis- Benzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (2- cyano -3- (3,5- bis- ((morpholinyl) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) - 7,7'- dimethoxy-4 's, 4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (2- cyano -3- (3- (morpholine methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- diformazans Oxygroup -4,4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (2- cyano -3- (3- ((diethylamino) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) - 7,7'- dimethoxy-4 's, 4' dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (2- cyano -3- (3,5- bis- ((1- pyrrolidinyls) methyl) -4- hydroxyls) phenyl -3- oxo -1- propylene Base) -7,7'- dimethoxy-4 's, 4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (2- cyano -3- (3- ((1- piperidyls) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7, 7'- dimethoxy-4 's, 4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (3- (3- methoxyl groups) phenyl -3- oxo -1- acrylic) -7,7'- dimethoxy-4 's, 4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates.
In particular, compound described in general formula I is further preferably from following compounds：
(E) -5'- (3- (3- ((diethylamino) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- two Methoxyl group -4,4' dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；(compound number：1a is similarly hereinafter)
(E) -5'- (3- (3- (((4- phenyl) piperazinyl) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7, 7'- dimethoxy-4 's, 4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；(1b)
(E) -5'- (3- (3,5- bis- (morpholinyl methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- diformazans Oxygroup -4,4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；(1c)
(E) -5'- (3- (3,5- bis- ((1- pyrrolidinyls) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7, 7'- dimethoxy-4 's, 4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；(1d)
(E) -5'- (3- (3- ((1- piperidyls) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- diformazans Oxygroup -4,4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；(1e)
(E) -5'- (3- (3- ((dimethylamino) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- two Methoxyl group -4,4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；(1f)
(E) -5'- (3- (3,5- bis- ((dimethylamino) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7, 7'- dimethoxy-4 's, 4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；(1g)
(E) -5'- (3- (3- ((1- pyrrolidinyls) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- two Methoxyl group -4,4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；(1h)
(E) -5'- (3- (3- (morpholine methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- dimethoxy-4 's, 4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；(1i)
(E) -5'- (3- (3- ((4- methyl piperazines base) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- Dimethoxy-4 ', 4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；(1j)
(E) -5'- (3- (3- methoxyl groups) phenyl -3- oxo -1- acrylic) -7,7'- dimethoxy-4 's, 4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates.(2a)
(E) -5'- (3- (3,4- dimethoxys) phenyl -3- oxo -1- acrylic) -7,7'- dimethoxy-4 's, 4'- hexichol And [d] [1,3] dioxa cyclopentenyl -5- methyl formates.(2b)
The invention discloses a kind of preparation methods of compound shown in general formula I, directly using Formula VII compound as raw material into Prepared by row, specific method is：Work as R1For-H, R2For phenyl or substituted-phenyl when, the preparation method packet of compound shown in general formula I Include step a) or step b)：
Work as R1For-H, R2For phenyl or substituted-phenyl when, the preparation method of compound shown in general formula I include step a) or step It is rapid b)：
A) Formula VII compound carries out aldol reaction with substituted acetophenone and generates compound of Formula I；Synthetic route is such as Under：
B) Formula VII compound first carries out aldol reaction with 4-hydroxyacetophenone and generates intermediate product VIII compounds, VIII compounds are reacted with formaldehyde and amine through Mannich again generates compound of Formula I；Synthetic route is as follows：
Work as R1For-CN, R2For phenyl or substituted-phenyl when, the preparation method of compound shown in general formula I include step c) or step It is rapid d)：
C) substituted methyl benzoate generates product IX with acetonitrile reaction, is then reacted with intermediate product VII and generates general formula Iization Object is closed, synthetic route is as follows：
D) intermediate VII and compound 3- (4- hydroxy phenyls) -3- oxo propionitriles generate compound X, X compound again with first Aldehyde and amine are reacted through Mannich generates compound of Formula I, and synthetic route is as follows：
Wherein, R R5、R6And R7。
The present invention further discloses a kind of preparation methods of compound shown in more specific general formula I：
Work as R1For-H, R2For substituted-phenyl when, the preparation method of compound shown in general formula I includes the following steps：Biphenyl is double Compound 7,7'- dimethoxy-4 's shown in Formula II, 4'- dibenzo [d] [1,3] dioxole -5,5'- two is made in ester hydrolysis Formic acid, Formula II compound and acetic anhydride production III compounds, formula III compound carry out alcoholysis reaction generation with methanol Formula IV compound 7,7'- dimethoxy -5'- methoxycarbonyls -4,4'- dibenzo [d] [1,3] dioxole -5- formic acid, Formula IV compound reacts production V compounds 5'- (1- carbonyls) imidazoles -7,7'- dimethoxy-4 's, 4'- dibenzo [d] with imidazoles [1,3] dioxole] -5- methyl formates, Formula V compound is through NaBH4Restore production VI compounds 5'- (1- hydroxyls) first Base -7,7'- dimethoxy-4 ', 4'- dibenzo [d] [1,3] dioxole -5- methyl formates, Formula IV compound is through PCC oxygen It is melted into intermediate product VII compound 5'- formoxyl -7,7'- dimethoxy-4 's, 4'- dibenzo [d] [1,3] dioxole - 5- methyl formates, synthetic route are as follows：
A) Formula VII compound carries out aldol reaction with substituted acetophenone and generates compound of Formula I；Synthetic route is such as Under：
B) Formula VII compound first carries out aldol reaction with 4-hydroxyacetophenone and generates intermediate product VIII compounds, VIII compounds are reacted with formaldehyde and amine through Mannich again generates compound of Formula I；Synthetic route is as follows：
Work as R1For-CN, R2For phenyl or substituted-phenyl when, the preparation method of compound shown in general formula I include step c) or step It is rapid d)：
C) substituted methyl benzoate generates product IX with acetonitrile reaction, is then reacted with intermediate product VII and generates general formula Iization Object is closed, synthetic route is as follows：
D) intermediate VII and compound 3- (4- hydroxy phenyls) -3- oxo propionitriles generate compound X, X compound again with first Aldehyde and amine are reacted through Mannich generates compound of Formula I, and synthetic route is as follows：
Wherein, R R5、R6And R7。
In by compound Bifendate prepare compounds VII or the reaction for preparing compound of Formula I by compound VII, Used solvent organic solvent is selected from dichloromethane, acetonitrile, tetrahydrofuran, pyridine, chloroform, toluene, dimethyl sulfoxide (DMSO) or two It is one or more in six ring of oxygen, it is preferred to use dichloromethane, acetonitrile, dioxane or tetrahydrofuran；The reaction temperature of use It is 0 DEG C to reflux.
In preparing V reactions by compound IV, used condensing agent is HATU, HBTU, HOBt, EDCI, DMAP, DCC, Preferentially use EDCI, DMAP；The reaction temperature used is room temperature.
In the reaction by compound V prepare compounds VI, used reducing agent is selected from sodium borohydride, lithium aluminium hydride, Preferentially use sodium borohydride；The reaction temperature used is 0 DEG C to room temperature.
In the reaction by compound VI prepare compounds VII, used oxidant is selected from manganese dioxide, hypochlorous acid Sodium, pyridinium chloro-chromate (PCC) or two pyridinium chloro-chromates (PDC) preferentially use pyridinium chloro-chromate (PCC)；What is used is anti- It is room temperature to answer temperature.
These intermediates or target compound can be purified according to conventional isolation techniques, and as needed by its turn Turn to the addition salts with pharmaceutically acceptable acid.
Unless otherwise stated, the following term used in the specification and in the claims has meaning discussed below：
" pharmaceutically acceptable salt " indicates to retain those of biological effectiveness and the property of parent compound salt.This kind of salt Including：
(1) it is obtained with inorganic acid or reacting for organic acid by the free alkali of parent compound, inorganic acid packet at salt with acid Include hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid and perchloric acid etc., organic acid include acetic acid, trifluoroacetic acid, Propionic acid, acrylic acid, caproic acid, pentamethylene propionic acid, oxyacetic acid, pyruvic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, Ascorbic acid, camphoric acid, benzoic acid, hydroxybenzoic acid, gamma-hydroxybutyric acid, methoxy benzoic acid, phthalic acid, methanesulfonic acid, Ethanesulfonic acid, naphthalene -1- sulfonic acid, naphthalene-2-sulfonic acid, p-methyl benzenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, cinnamic acid, dodecane Base sulfuric acid, gluconic acid, glutamic acid, aspartic acid, stearic acid, mandelic acid, succinic acid, glutaric acid or malonic acid etc..
(2) acid proton being present in parent compound is replaced or given birth to organic base ligand compound by metal ion At salt, metal ion such as alkali metal ion, alkaline-earth metal ions or aluminium ion, organic bases for example ethanol amine, diethanol amine, Triethanolamine, tromethamine, N-METHYL-ALPHA-L-GLUCOSAMINE, quinine etc..
" pharmaceutical composition " refers to one or more of compound in the present invention or its pharmaceutically acceptable salt, molten Agent compound, hydrate or prodrug and other chemical composition, such as pharmaceutically acceptable carrier, mixing.The mesh of pharmaceutical composition Be promote administration to animal process.
" pharmaceutical carrier " or " pharmaceutically acceptable carrier " refers to not causing organism apparent irritation and not Non-active ingredient in the bioactivity of the given compound of interference and the pharmaceutical composition of property, such as, but not limited to：Carbonic acid Calcium, calcium phosphate, various sugared (such as lactose, mannitol etc.), starch, cyclodextrin, magnesium stearate, cellulose, magnesium carbonate, acrylic acid Polymer or methacrylate polymer, gel, water, polyethylene glycol, propylene glycol, ethylene glycol, castor oil or rilanit special or More ethoxy aluminium castor oil, sesame oil, corn oil, peanut oil etc..
" alkyl " indicates that the aliphatic group of the saturation of 1-20 carbon atom, including straight chain and branched group (carry in this specification The digital scope arrived, such as " 1-20 " refer to the group, are at this time alkyl, can contain 1 carbon atom, 2 carbon atoms, 3 carbon Atom etc., until including 20 carbon atoms).It is further preferred that alkyl is the medium sized alkyl for having 1-10 carbon atom, example Such as methyl, ethyl, propyl, 2- propyl, normal-butyl, isobutyl group, tertiary butyl, amyl.Preferably, alkyl is to have 1-8 or 1-6 Low alkyl group of carbon atom, such as methyl, ethyl, propyl, 2- propyl, normal-butyl, isobutyl group or tertiary butyl etc..Alkyl can be It is substituted or unsubstituted.When being the alkyl of substitution, which is preferably one or more, more preferable 1-3, and most preferably 1 Or 2 substituent groups.
" alkylidene " indicates the aliphatic group of the saturation for 1-20 carbon atom being connected with two groups, including straight chain and branch (digital scope mentioned in this specification, such as " 1-20 " refer to the group to chain group, are at this time alkylidene, can contain 1 Carbon atom, 2 carbon atoms, 3 carbon atoms etc., until including 20 carbon atoms).It is further preferred that alkylidene is that have 1-10 The medium sized alkylidene of carbon atom, for example, methylene, ethylidene, propylidene, Asia 2- propyl, sub- normal-butyl, sub- tertiary butyl, Amyl etc..Preferably, alkyl is the low-grade alkylidene for having 1-8 or 1-6 carbon atom.Alkylidene can be substitution or unsubstituted 's.When being the alkylidene of substitution, which is preferably one or more, more preferable 1-3, most preferably 1 or 2 substituent group.
" aromatic heterocycle " or " heteroaryl " indicate 5 to 12 annular atoms monocycle or fused ring group, contain there are one, two A, three or four ring hetero atoms for being selected from N, O or S, remaining annular atom is C, in addition the pi-electron system with total conjugated. Unsubstituted heteroaryl base non-limiting examples have pyrroles, furans, thiophene, imidazoles, oxazole, thiazole, pyrazoles, pyridine, pyrimidine, quinoline Quinoline, isoquinolin, purine, tetrazolium, triazine and carbazole.Heteroaryl can be substituted or unsubstituted.When substituted, substituent group Preferably one or more, more preferably one, two or three, and then it is more highly preferred to one or two, independently selected from Following group, including：Low alkyl group, three alkylhalide groups, halogen, hydroxyl, lower alkoxy, sulfydryl, (low alkyl group) sulfenyl, cyanogen Base, acyl group, Thioacyl, O- carbamoyls, N- carbamoyls, O- thiocarbamoyls, N- thiocarbamoyls, C- acylamino-s, N- acylamino-s, nitro, N- sulfonamidos, S- sulfonamidos.Preferred heteroaryl is optionally taken by one or two Replace for base, substituent group is independently selected from halogen, low alkyl group, three alkylhalide groups, hydroxyl, sulfydryl, cyano, N- acylamino-s, Dan Huo Dialkyl amino, carboxyl or N- sulfonamidos.
" heteroalicyclyl " indicates monocycle or fused ring group, has 5 to 9 annular atoms in ring, wherein one or two Annular atom is to be selected from N, O or S (O)mThe hetero atom of (wherein m is 0 to 2 integer), remaining annular atom is C.These rings can have There is one or more double bond, but these rings do not have the pi-electron system of total conjugated.Unsubstituted heteroalicyclyl it is non-limiting Example has pyrrolidinyl, piperidino, Piperazino, morpholino base etc..
" hydroxyl " expression-OH groups.
" nitro " expression-NO2Group.
" cyano " expression-CN groups.
" alkoxy " expression-O- (unsubstituted alkyl) and-O- (unsubstituted naphthenic base).Representative example includes but not It is limited to methoxyl group, ethyoxyl, propoxyl group, butoxy, ring propoxyl group, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc..
" halogen " indicates fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
" halogenated alkyl " indicates the alkyl of halogen substitution, the low alkyl group of halogen substitution preferably as defined above, its quilt One or more identical or different halogen atom substitutions, such as-CH2Cl ,-CF3 ,-CH2CF3 ,-CH2CCl3 etc..
" optional " or " optionally " mean event described later or environment can with but need not occur, which includes The occasion that the event or environment occur and do not occur.For example, " heteroaryl is optionally replaced by one or two substituent group " is meaned Heteroaryl substituent group can with but need not be one, which includes the situation and heteroaryl that heteroaryl is replaced by a substituent group The situation that base is replaced by two substituent groups.
The present invention provides a kind of pharmaceutical compositions, it is to live with the compound of the present invention or its pharmaceutically acceptable salt Property ingredient or main active, are aided with pharmaceutically acceptable carrier.
The compound of the present invention or its pharmaceutically acceptable salt can be applied to prepare and the anti-oxidant drug for having related disorders Aspect, in terms of being especially used to prepare anti-inflammatory drug or anti-oxidation medicine.
Description of the drawings
Fig. 1 is that representation compound of the present invention improves antioxidant genes HO-1 (A), NQO1 (B), the mRNA level in-site of SOD (C) Experiment；
Fig. 2 is the dose-dependent raising antioxidant genes HO-1 (A) of representation compound of the present invention energy of various dose, The protein level of NQO1 (B).
Specific implementation mode
In order to which the present invention is furture elucidated, a series of embodiments are given below, these embodiments be entirely it is illustrative, it Only be used for the present invention specifically describe, be not construed as limitation of the present invention.
Embodiment 1
5'- (1- carbonyls) imidazoles -7,7'- dimethoxy-4 's, 4'- dibenzo [d] [1,3] dioxole] -5- formic acid Methyl esters (VI)
Bifendate, NaOH are placed in that compound IV (2g, 5.0mmol), that imidazoles (404mg, 5.9mmol) is placed in 50mL is anhydrous CH2Cl2In, after reaction 2h is stirred at room temperature in addition EDCI (1.1g, 5.9mmol), DMAP (61mg, 0.5mmol), add water stratification, CH2Cl2Extraction.Organic layer uses the HCl of 1N respectively, is saturated NaHCO3And saturated common salt water washing, anhydrous Na2SO4It is dry, filtering, Compound V (2.14g, 95%) is obtained after decompression removal solvent.The compound is known compound.(Bioorganic& Medicinal Chemistry 20(2012)2540–2548)m.p.68-70℃；ESI-MS:m/z:477 [M+Na]+chemical combination Object V directly casts single step reaction without purifying.
Compound V (2g, the 4.4mmol) THF of 30mL are dissolved, ice bath cooling.Weigh NaBH4(332mg, It 8.8mmol) is placed in constant pressure funnel, (note is cooled down in solution with the THF for being slowly added drop-wise to compound V after water dissolution：This Process has bulk gas generation).The HCl tune pH values of 2N are slowly added dropwise after faintly acid, to subtract in TLC tracking reactions after reaction It pushes back after receiving major part THF, reaction solution is extracted with ethyl acetate, organic layer is respectively with saturation NaHCO3, saturated common salt water washing, Anhydrous Na2SO4It is dry.Recycling design obtains crude product, Flash silica column chromatography for separation (PE/EtOAc=5:3, V/V) white centre is obtained Body VI (1.6g, 92%).The compound is known compound.(Bioorganic&Medicinal Chemistry 20(2012) 2540–2548).m.p.126-128℃；ESI-MS m/z:413[M+Na]+；1H-NMR(CDCl3,300MHz,δppm):3.71 (s,3H,COOCH3),3.95(s,3H,ArOCH3),3.97(s,3H,ArOCH3),4.35(d,1H,CH2OH, J=12Hz), 4.40(d,1H,CH2OH, J=12Hz), 5.91-6.04 (m, 4H, 2 × OCH2O),6.78(s,1H,Ar-H),7.33(s,1H, Ar-H).
Embodiment 2
5'- formoxyl -7,7'- dimethoxy-4 's, 4'- dibenzo [d] [1,3] dioxole -5- methyl formates (VII)
Compound VI (1.5g, 3.8mmol) is placed in constant pressure funnel, with the CH of 30mL2Cl2Then dissolving is slowly dripped Enter the CH of PCC (900mg, 4.2mmol)2Cl2In suspension (ice bath cooling), recovery is added dropwise to reaction is stirred at room temperature.TLC Reaction process is tracked, after reaction, reaction solution is filtered with diatomite (or silica gel), and filtrate is concentrated to dryness to obtain crude product.Quick silicon Plastic column chromatography isolates and purifies (PE/EtOAc=3:1, V/V) white intermediate VII (1.46g, 98%) is obtained.The compound is known Compound.(Bioorganic&Medicinal Chemistry 20(2012)2540–2548).αm.p.179-181℃；1H- NMR(CDCl3,300MHz,δppm):3.68(s,3H,COOCH3),3.98(s,3H,ArOCH3),3.99(s,3H,ArOCH3), 6.01-6.10(m,4H,2×OCH2O),7.32(s,1H,Ar-H),7.42(s,1H,Ar-H)；
Embodiment 3
(E) -5'- (3- (3- methoxyl groups) phenyl -3- oxo -1- acrylic) -7,7'- dimethoxy-4 's, 4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates (2a)
Intermediate VII (100mg, 0.26mmol) and the anhydrous 1,4- dioxane of 3- methoxyacetophenones (0.31mmol) After dispersion, air is taken out in argon gas protection, is slowly added dropwise into BF3.Et2O solution (105 μ L, 0.39mmol), reaction solution becomes yellow.Nitrogen It is started to warm up under gas shielded to 4-5h is reacted at 70 DEG C, TLC tracking reactions, (reaction solution is peony at this time) will after reaction Reaction solution is cooled to room temperature, and adds water stratification, ethyl acetate extraction.Organic layer with saturated common salt water washing for several times, anhydrous Na2SO4It is dry It is dry.Filtering, is removed under reduced pressure solvent afforded crude material.Flash silica column chromatography (PE/EtOAc=5:1-1:1, V/V) purifying obtains yellow Target compound 2a, yield 85%.ESI-MS:m/z 520.9([M+H]+)；1H-NMR(CDCl3,400MHz,δppm):3.66 (s,3H,Ar-OCH3)3.84(s,3H,Ar-OCH3),3.98(s,3H),3.99(s,3H,Ar-OCH3),6.04–5.95(m,4H, 2×-OCH2), O- 7.06 (s, 1H, Ar-H), 7.09 (d, 1H, Ar-H, J=2.7Hz), 7.21 (s, 1H, Ar-H), 7.34 (t, 1H, Ar-H, J=7.9Hz), 7.40 (s, 1H, Ar-H), 7.42-7.40 (m, 1H, Ar-H), 7.45 (d, 1H, Ar-H, J= 7.7Hz), 7.55 (d, 1H, CH=CHCO, J=15.6Hz)
Embodiment 4
(E) -5'- (3- (3,4- dimethoxys) phenyl -3- oxo -1- acrylic) -7,7'- dimethoxy-4 's, 4'- hexichol And [d] [1,3] dioxa cyclopentenyl -5- methyl formates (2b)
By the similar approach of embodiment 3, intermediate VII, 3,4- dimethoxy-acetophenones, BF3.Et2Yellow is obtained by the reaction in O Target compound.ESI-MS:m/z 550.9[M+H]+；1H-NMR(CDCl3,400MHz,δppm):3.66(s,3H,Ar- OCH3),3.92(s,3H,Ar-OCH3),3.94(s,3H),3.97(s,3H,Ar-OCH3),4.00(s,3H,Ar-OCH3), 6.02–5.95(m,4H,2×-OCH2), O- 6.87 (d, 1H, Ar-H, J=8.3Hz), 7.06 (s, 1H, Ar-H), 7.27 (d, 1H, CH=CHCO, J=15.6Hz), 7.40 (s, 1H, Ar-H), 7.51 (d, 1H, Ar-H, J=1.9Hz), 7.52 (d, 1H, Ar-H, J=1.9Hz), 7.57-7.53 (m, 1H, Ar-H)
Embodiment 5
(E) -5'- (3- (3- ((diethylamino) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- two Methoxyl group -4,4' dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates (1a)
By intermediate VII and 4-hydroxyacetophenone product (E) -5'- (3- (4- hydroxyls are prepared according to the similar approach of embodiment 3 Base) phenyl -3- oxo -1- acrylic) -7,7'- dimethoxy-4 's, 4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- first Sour methyl esters VIII, yield 72% is yellow solid powder, which is known compound.(Bioorganic&Medicinal Chemistry 20(2012)2540–2548).m.p.248-250℃；ESI-MS:m/z 507.0[M+H]+.Compound VIII (100mg, 0.2mmol) is dissolved with DMSO, and 30% formalin (55 μ L, 0.6mmol) is added, diethylamine salt is then added Hydrochlorate (0.3mmol) and Et3N (0.3mmol) (notes：If secondary-amine compound is hydrochloride, addition etc. is needed to rub The Et of your amount3N adjusts PH), 5h is reacted at 90 DEG C, TLC tracking reactions are cooled to room temperature, acetic acid is used after adding water after reaction Ethyl ester extracts, organic layer saturated common salt water washing, anhydrous Na2SO4It is dry.Filtering, is removed under reduced pressure solvent afforded crude material.Flash silica Column chromatographic isolation and purification (first CH2Cl2/ EtOAc=4:1-1:1, rear CH2Cl2/ MeOH=10:1-1:1) production of yellow target, is obtained Object, yield 58%.m.p.74-76℃；ESI-MS:m/z 592.3[M+H]+；1H-NMR(CDCl3,300MHz,δppm):1.13 (t, 6H, 2 × CH3, J=6.9Hz), 2.62-2.70 (m, 4H, 2 × NCH2),3.66(s,3H,COOCH3),3.83(s,2H, ArCH2),3.99(s,3H,ArOCH3),4.00(s,3H,ArOCH3),5.98-6.03(m,4H,2×OCH2O),6.80(d,1H, Ar-H, J=8.2Hz), 7.06 (s, 1H, Ar-H), 7.25 (d, 1H, CH=CHCO, J=15.4Hz), 7.41 (s, 1H, Ar-H), 7.53 (d, 1H, CH=CHCO, J=15.4Hz), 7.65 (s, 1H, Ar-H), 7.76 (d, 1H, Ar-H, J=8.2Hz)
Embodiment 6
(E) -5'- (3- (3- (((4- phenyl) piperazinyl) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7, 7'- dimethoxy-4 's, 4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates (1b)
According to the similar approach of embodiment 5, the yellow solid powder prepared by compound VIII and formaldehyde and N-benzyl piperazine End, yield 57%.m.p.91-93℃；ESI-MS:m/z 695.4[M+H]+；1H-NMR(CDCl3,300MHz,δppm):2.30- 2.64(m,8H,4×NCH2),3.77(s,2H,ArCH2),3.66(s,3H,COOCH3),3.77(s,2H,ArCH2),3.98(s, 3H,ArOCH3),4.00(s,3H,ArOCH3),5.97-6.04(m,4H,2×OCH2), O 6.82 (d, 1H, Ar-H, J= 8.3Hz), 7.05 (s, 1H, Ar-H), 7.20-7.40 (m, 6H, CH=CHCO, 5 × ArH), 7.41 (s, 1H, Ar-H), 7.53 (d, 1H, CH=CHCO, J=15.5Hz), 7.63 (s, 1H, Ar-H), 7.77 (d, 1H, Ar-H, J=8.3Hz)
Embodiment 7
(E) -5'- (3- (3,5- bis- (morpholinyl methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- diformazans Oxygroup -4,4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates (1c)
According to the similar approach of embodiment 5, the yellow solid powder prepared by compound VIII and formaldehyde and morpholine, yield 87%.m.p.90-92℃；ESI-MS:m/z 705.3[M+H]+；1H-NMR(CDCl3,300MHz,δppm):2.56(s,8H,4 ×NCH2),3.67(s,7H,2×ArCH2COOCH3),3.75(s,8H,4×OCH2),3.99(s,3H,ArOCH3),4.02(s, 3H,ArOCH3), 5.98-6.06 (m, 4H, 2 × OCH2O), 7.07 (s, 1H, Ar-H), 7.28 (d, 1H, CH=CHCO, J= 15.0Hz), 7.41 (s, 1H, Ar-H), 7.54 (d, 1H, CH=CHCO, J=15.0Hz), 7.71 (s, 1H, Ar-H)
Embodiment 8
(E) -5'- (3- (3,5- bis- ((1- pyrrolidinyls) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7, 7'- dimethoxy-4 's, 4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates (1d)
According to the similar approach of embodiment 5, the yellow solid powder prepared by compound VIII and formaldehyde and pyrrolidines is received Rate 72%.m.p.90-92℃；ESI-MS:m/z 673.3[M+H]+；1H-NMR(CDCl3,300MHz,δppm):1.81-1.94 (m,8H,4×CH2),2.65-2.78(m,8H,4×NCH2),3.65(s,3H,COOCH3),3.87(s,4H,2×ArCH2), 3.98(s,3H,ArOCH3),4.05(s,3H,ArOCH3),5.98-6.06(m,4H,2×OCH2O),7.09(s,1H,Ar-H), 7.34-7.45 (m, 2H, Ar-H, CH=CHCO), 7.56 (d, 1H, CH=CHCO, J=15.4Hz), 7.78 (s, 2H, Ar-H)
Embodiment 9
(E) -5'- (3- (3- ((1- piperidyls) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- diformazans Oxygroup -4,4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates (1e)
According to the similar approach of embodiment 5, the yellow solid powder prepared by compound VIII and formaldehyde and piperidines, yield 66%.m.p.100-102℃；ESI-MS:m/z 604.3[M+H]+；1H-NMR(CDCl3,300MHz,δppm):1.42-1.79 (m,6H,3×CH2),2.33-2.73(m,4H,2×NCH2),3.66(s,3H,COOCH3),3.74(s,2H,ArCH2),3.99 (s,3H,ArOCH3),4.01(s,3H,ArOCH3), 5.97-6.01 (m, 4H, 2 × OCH2O), 6.82 (d, 1H, Ar-H, J= 8.1Hz), 7.06 (s, 1H, Ar-H), 7.25 (d, 1H, CH=CHCO, J=15.5Hz), 7.41 (s, 1H, Ar-H), 7.53 (d, 1H, CH=CHCO, J=15.5Hz), 7.65 (s, 1H, Ar-H), 7.76 (d, 1H, Ar-H, J=8.1Hz)
Embodiment 10
(E) -5'- (3- (3- ((dimethylamino) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- two Methoxyl group -4,4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates (1f)
According to the similar approach of embodiment 5, the Huang prepared by compound VIII and formaldehyde and dimethylamine hydrochloride, triethylamine Color solid powder, yield 56%.m.p.83-85℃；ESI-MS:m/z 564.3[M+H]+；1H-NMR(CDCl3,300MHz,δ ppm):2.37(s,6H,2×NCH3),3.66(s,3H,COOCH3),3.72(s,2H,ArCH2),3.99(s,3H,ArOCH3), 4.01(s,3H,ArOCH3),5.97-6.01(m,4H,2×OCH2), O 6.83 (d, 1H, Ar-H, J=8.1Hz), 7.06 (s, 1H, ), Ar-H 7.26 (d, 1H, CH=CHCO, J=15.5Hz), 7.41 (s, 1H, Ar-H), 7.53 (d, 1H, CH=CHCO, J= 15.5Hz), 7.65 (s, 1H, Ar-H), 7.84 (d, 1H, Ar-H, J=8.1Hz) ESI-MS:m/z 564.3[M+H]+.
Embodiment 11
(E) -5'- (3- (3,5- bis- ((dimethylamino) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7, 7'- dimethoxy-4 's, 4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates (1g)
According to the similar approach of embodiment 5, the Huang prepared by compound VIII and formaldehyde and dimethylamine hydrochloride, triethylamine Color solid powder, yield 88%.m.p.82-84℃；ESI-MS:m/z 621.4[M+H]+；1H-NMR(CDCl3,300MHz,δ ppm):2.34(s,12H,4×NCH3),3.64(s,3H,COOCH3),3.66(s,4H,2×ArCH2),3.98(s,3H, ArOCH3),4.03(s,3H,ArOCH3),5.98-6.01(m,4H,2×OCH2O),7.12(s,1H,Ar-H),7.34-7.42 (m, 2H, Ar-H, CH=CHCO), 7.56 (d, 1H, CH=CHCO, J=15.4Hz), 7.72 (s, 2H, Ar-H)
Embodiment 12
(E) -5'- (3- (3- ((1- pyrrolidinyls) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- two Methoxyl group -4,4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates (1h)
According to the similar approach of embodiment 5, the yellow solid powder prepared by compound VIII and formaldehyde and pyrrolidines is received Rate 62%.m.p.103-105℃；ESI-MS:m/z 590.2[M+H]+；1H-NMR(CDCl3,300MHz,δppm):1.81- 1.92(m,4H,2×CH2),2.58-2.73(m,4H,2×NCH2),3.66(s,3H,COOCH3),3.89(s,2H,ArCH2), 3.99(s,3H,ArOCH3),4.00(s,3H,ArOCH3),5.97-6.02(m,4H,2×OCH2O),6.82(d,1H,Ar-H,J =8.2Hz), 7.07 (s, 1H, Ar-H), 7.26 (d, 1H, CH=CHCO, J=15.5Hz), 7.41 (s, 1H, Ar-H), 7.53 (d, 1H, CH=CHCO, J=15.5Hz), 7.66 (s, 1H, Ar-H), 7.84 (d, 1H, Ar-H, J=8.0Hz)
Embodiment 13
(E) -5'- (3- (3- (morpholine methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- dimethoxy-4 's, 4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates (1i)
According to the similar approach of embodiment 5, the yellow solid powder prepared by compound VIII and formaldehyde and morpholine, yield It is 67%.m.p.93-95℃；ESI-MS:m/z 606.2[M+H]+；1H-NMR(CDCl3,300MHz,δppm):2.60(s,4H, 2×NCH2),3.67(s,5H,ArCH2,COOCH3),3.77(s,4H,2×OCH2),3.98(s,3H,ArOCH3),4.00(s, 3H,ArOCH3),5.90-6.01(m,4H,2×OCH2), O 6.84 (d, 1H, Ar-H, J=8.4Hz), 7.07 (s, 1H, Ar-H), 7.24 (d, 1H, CH=CHCO, J=15.0Hz), 7.40 (s, 1H, Ar-H), 7.54 (d, 1H, CH=CHCO, J=15.0Hz), 7.67(s,1H,Ar-H),7.76-7.87(m,1H,Ar-H).
Embodiment 14
(E) -5'- (3- (3- ((4- methyl piperazines base) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- Dimethoxy-4 ', 4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates (1j)
According to the similar approach of embodiment 5, the yellow solid powder prepared by compound VIII and formaldehyde and N methyl piperazine End, yield 70%.m.p.88-90℃；ESI-MS:m/z 641.3[M+Na]+；1H-NMR(CDCl3,300MHz,δppm):2.34 (s,3H,CH3),2.45-2.75(m,8H,4×NCH2),3.66(s,3H,COOCH3),3.72(s,2H,ArCH2),3.99(s, 3H,ArOCH3),4.04(s,3H,ArOCH3),5.98-6.05(m,4H,2×OCH2O),7.12(s,1H,Ar-H),7.37- 7.41 (m, 1H, CH=CHCO), 7.41 (s, 1H, Ar-H), 7.56 (d, 1H, CH=CHCO, J=15.4Hz), 7.69-7.75 (m,2H,Ar-H).
Embodiment 15
Here is the part pharmacological testing and result of the representation compound of the present invention：
1, Compounds Against oxidoreductase gene HO-1, NQO1, the influence of the mRNA level in-site of SOD
Using PCR method detection compound act on 24 hours to Nrf2 downstream genes NQO-1 (quinone oxidoreductase -1), The influence of HO-1 (Heme oxygeanse-1), SOD (superoxide dismutase) expression, n=4, NC are normal group, Res (white black false hellebores Alcohol) it is positive controls, a concentration of 10uM, H2O2For model group, a concentration of 400uM, compound concentration 10uM.Mean± P≤0.01 SD, * P≤0.05, * *, compared with NC groups.
As shown in Figure 1, compound 1a, 1b, 1c, 1d and 1e can significantly improve antioxidant genes HO-1 compared to normal group, The expression of the mRNA level in-site of NQO1, SOD, other compounds such as 1f, 1g, 1h, 1i, 1j, 2a, 2b have similar experiment effect, Wherein compound 1c significant effects.
2, the influence of Compounds Against oxidoreductase gene HO-1, the NQO1 protein level of various dose
Using Western blot methods in protein level detection various dose Compounds Against oxidoreductase gene HO-1, NQO1 The influence of expression.DMSO is normal group, and Res (resveratrol) is positive controls, a concentration of 10uM, H2O2For oxidative damage mould Type group, H2O2A concentration of 400uM, compound concentration are respectively 5uM (M), 10uM (H), Mean ± SD, n=4, * P≤0.05, * * P ≤ 0.01, compared with DMSO and Res groups.
As shown in Fig. 2, compound 1c and 1d can significantly improve antioxidant genes compared to normal group and positive controls The expression of HO-1, NQO1 protein level, other compounds such as 1a, 1b, 1e, 1f, 1g, 1h, 1i, 1j, 2a, 2b have similar reality Effect, wherein compound 1c significant effects are tested, and shows dose dependent.

Claims (10)

1. alkoxy biphenyl shown in Formulas I/chalcone heterozygosis class compound or its pharmaceutically acceptable salt,
Wherein,
R1Represent hydrogen atom, cyano, nitro, hydroxyl or halogen；
R2Phenyl, substituted-phenyl or substitution heteroaromatic are represented, the substituted-phenyl or substitution heteroaromatic can arbitrarily be taken by following It is monosubstituted or polysubstituted for base：C1-C4Alkoxy, C1-C4Alkyl, hydroxyl, halogen or-(CH2)nNR3R4；
N represents the integer of 1-3；
R3Or R4Separately represent C1-C6Alkyl or NR3R45 to 7 yuan of substituted or non-substituted aliphatic heterocycles are formed together； Its substituent group is selected from C1-C4Alkyl, phenyl or benzyl.
2. compound according to claim 1 or its pharmaceutically acceptable salt, wherein R2Represent following radicals：
R5Represent hydrogen atom, hydroxyl or C1-C4Alkoxy；
R6Or R7Separately represent hydrogen atom, C1-C4Alkoxy, halogen or-(CH2)nNR3R4。
3. compound according to claim 2 or its pharmaceutically acceptable salt, wherein R5Represent hydroxyl or C1-C4Alcoxyl Base；R6Represent hydrogen atom or-(CH2)nNR3R4；R7Represent hydrogen atom, C1-C4Alkoxy or-(CH2)nNR3R4。
4. compound according to claim 1,2 or 3 or its pharmaceutically acceptable salt, wherein R3Or R4Separately Represent C1-C4Alkyl or NR3R45 to 7 yuan of substituted or non-substituted aliphatic heterocycles are formed together；Its substituent group is selected from C1-C3Alkane Base, phenyl or benzyl.
5. compound according to claim 4 or its pharmaceutically acceptable salt, wherein 5 to 7 yuan of aliphatic heterocycles select From morpholine ring, piperazine ring, pyrrole ring or piperidine ring.
6. compound according to claim 1,2 or 3 or its pharmaceutically acceptable salt, are selected from wherein stating compound：
(E) -5'- (3- (3- ((dimethylamino) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- dimethoxies Base -4,4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (3- (3,5- bis- ((dimethylamino) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- two Methoxyl group -4,4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (3- (3- ((diethylamino) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- dimethoxies Base -4,4' dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (3- (3- ((1- pyrrolidinyls) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- dimethoxies Base -4,4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (3- (3,5- bis- ((1- pyrrolidinyls) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- two Methoxyl group -4,4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (3- (3- (morpholine methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- dimethoxy-4 's, 4'- Dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (3- ((the morpholine methyl) -4- of 3,5- bis- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- dimethoxy-4 's, 4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (3- (3- ((4- methyl piperazines base) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- diformazans Oxygroup -4,4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (3- (3- (((4- phenyl) piperazinyl) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- two Methoxyl group -4,4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (3- (3- ((1- piperidyls) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- dimethoxys - 4,4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (3- (3,4- dimethoxys) phenyl -3- oxo -1- acrylic) -7,7'- dimethoxy-4 's, 4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (3- (3,5- bis- ((diethylamino) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- two Methoxyl group -4,4' dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (2- cyano -3- (3,4- dimethoxys) phenyl -3- oxo -1- acrylic) -7,7'- dimethoxy-4 's, 4'- Dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (2- cyano -3- (4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- dimethoxy-4 's, 4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (2- cyano -3- (3,5- bis- ((morpholinyl) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- Dimethoxy-4 ', 4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (2- cyano -3- (3- (morpholine methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- dimethoxies Base -4,4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (2- cyano -3- (3- ((diethylamino) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- Dimethoxy-4 ', 4' dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (2- cyano -3- (3,5- bis- ((1- pyrrolidinyls) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) - 7,7'- dimethoxy-4 's, 4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (2- cyano -3- (3- ((1- piperidyls) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- two Methoxyl group -4,4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (3- (3- methoxyl groups) phenyl -3- oxo -1- acrylic) -7,7'- dimethoxy-4 's, 4'- dibenzo [d] [1, 3] dioxa cyclopentenyl -5- methyl formates.
7. compound according to claim 1,2 or 3 or its pharmaceutically acceptable salt, are selected from wherein stating compound：
(E) -5'- (3- (3- ((diethylamino) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- dimethoxies Base -4,4' dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (3- (3- (((4- phenyl) piperazinyl) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- two Methoxyl group -4,4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (3- (3,5- bis- (morpholinyl methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- dimethoxys - 4,4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (3- (3,5- bis- ((1- pyrrolidinyls) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- two Methoxyl group -4,4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (3- (3- ((1- piperidyls) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- dimethoxys - 4,4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (3- (3- ((dimethylamino) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- dimethoxies Base -4,4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (3- (3,5- bis- ((dimethylamino) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- two Methoxyl group -4,4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (3- (3- ((1- pyrrolidinyls) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- dimethoxies Base -4,4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (3- (3- (morpholinyl methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- dimethoxy-4 's, 4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (3- (3- ((4- methyl piperazines base) methyl) -4- hydroxyls) phenyl -3- oxo -1- acrylic) -7,7'- diformazans Oxygroup -4,4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (3- (3- methoxyl groups) phenyl -3- oxo -1- acrylic) -7,7'- dimethoxy-4 's, 4'- dibenzo [d] [1, 3] dioxa cyclopentenyl -5- methyl formates；
(E) -5'- (3- (3,4- dimethoxys) phenyl -3- oxo -1- acrylic) -7,7'- dimethoxy-4 's, 4'- dibenzo [d] [1,3] dioxa cyclopentenyl -5- methyl formates.
8. a kind of preparation method of compound described in claim 1, which is characterized in that
Work as R1For-H, R2For phenyl or substituted-phenyl when, the preparation method of compound shown in general formula I includes step a) or step b)：
A) Formula VII compound carries out aldol reaction with substituted acetophenone and generates compound of Formula I；Synthetic route is as follows：
B) Formula VII compound first carries out aldol reaction with 4-hydroxyacetophenone and generates intermediate product VIII compounds, VIII Compound is reacted with formaldehyde and amine through Mannich again generates compound of Formula I；Synthetic route is as follows：
Work as R1For-CN, R2For phenyl or substituted-phenyl when, the preparation method of compound shown in general formula I includes step c) or step d)：
C) substituted methyl benzoate generates product IX with acetonitrile reaction, is then reacted with intermediate product VII and generates general formula I chemical combination Object, synthetic route are as follows：
D) intermediate VII and compound 3- (4- hydroxy phenyls) -3- oxo propionitriles generate compound X, X compound again with formaldehyde and Amine is reacted through Mannich generates compound of Formula I, and synthetic route is as follows：
Wherein, R R5、R6And R7。
9. a kind of pharmaceutical composition, it is using compound described in claim 1 or its pharmaceutically acceptable salt as active constituent Or main active, it is aided with pharmaceutically acceptable carrier.
10. compound as claimed in claim 1,2 or 3 or its pharmaceutically acceptable salt have related disorders preparing with anti-oxidant Application in terms of drug, the application especially in terms of preparing anti-inflammatory drug or anti-oxidation medicine.
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